Alkyne and alkene derivatives as sphingosine 1-phosphate-1 receptor modulators

ABSTRACT

The present invention relates to novel alkyne and alkene derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. patent application Ser. No.13/305,398, filed Nov. 28, 2011, which claims the benefit of U.S.Provisional Application Ser. No. 61/419,278 filed Dec. 3, 2010, both ofwhich are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel alkyne and alkene derivatives,processes for preparing them, pharmaceutical compositions containingthem and their use as pharmaceuticals, as modulators ofsphingosine-1-phosphate receptors. The invention relates specifically tothe use of these compounds and their pharmaceutical compositions totreat disorders associated with sphingosine-1-phosphate (S1P) receptormodulation.

BACKGROUND OF THE INVENTION

Sphingosine-1 phosphate is stored in relatively high concentrations inhuman platelets, which lack the enzymes responsible for its catabolism,and it is released into the blood stream upon activation ofphysiological stimuli, such as growth factors, cytokines, and receptoragonists and antigens. It may also have a critical role in plateletaggregation and thrombosis and could aggravate cardiovascular diseases.On the other hand the relatively high concentration of the metabolite inhigh-density lipoproteins (HDL) may have beneficial implications foratherogenesis. For example, there are recent suggestions thatsphingosine-1-phosphate, together with other lysolipids such assphingosylphosphorylcholine and lysosulfatide, are responsible for thebeneficial clinical effects of HDL by stimulating the production of thepotent antiatherogenic signaling molecule nitric oxide by the vascularendothelium. In addition, like lysophosphatidic acid, it is a marker forcertain types of cancer, and there is evidence that its role in celldivision or proliferation may have an influence on the development ofcancers. These are currently topics that are attracting great interestamongst medical researchers, and the potential for therapeuticintervention in sphingosine-1-phosphate metabolism is under activeinvestigation.

SUMMARY OF THE INVENTION

A group of novel alkyne and alkene derivatives which are potent andselective sphingosine-1-phosphate modulators has been discovered. Assuch, the compounds described herein are useful in treating a widevariety of disorders associated with modulation ofsphingosine-1-phosphate receptors. The term “modulator” as used herein,includes but is not limited to: receptor agonist, antagonist, inverseagonist, inverse antagonist, partial agonist, partial antagonist.

This invention describes compounds of Formula I, which havesphingosine-1-phosphate receptor biological activity. The compounds inaccordance with the present invention are thus of use in medicine, forexample in the treatment of humans with diseases and conditions that arealleviated by S1P modulation.

In one aspect, the invention provides a compound having Formula I or apharmaceutically acceptable salt thereof or stereoisomeric formsthereof, or the geometrical isomers, enantiomers, diastereoisomers,tautomers, zwitterions and pharmaceutically acceptable salts thereof:

wherein:“

” represents a double bond “—CR¹⁴═CR¹⁵—” or a triple bond “—C≡C—”;A is C₆₋₁₀ aryl, heterocycle, C₃₋₈ cycloakyl or C₃₋₈ cycloalkenyl;B is C₆₋₁₀ aryl, heterocycle, C₃₋₈ cycloakyl or C₃₋₈ cycloalkenyl;R¹ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;R² is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;R³ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;R⁴ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;R⁵ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;R⁶ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;R⁷ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, C₆₋₁₀ aryl,heterocycle, C₃₋₈ cycloakyl, C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;R⁸ is the same or independently halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN,C(O)R¹¹, NR¹²R¹³ or hydroxyl;

L¹ is O, S, NH or CH₂;

R⁹ is H or C₁₋₆ alkyl;

L² is CHR¹⁴ or O;

R¹⁰ is H, OPO₃H₂, carboxylic acid, hydroxyl, PO₃H₂, —S(O)₂H, —P(O)MeOHor —P(O)(H)OH;R¹¹ is H or C₁₋₈ alkyl;a is 0, 1, 2 or 3;b is 0 or 1;R¹² is H or C₁₋₈ alkyl;R¹³ is H or C₁₋₈ alkyl;R¹⁴ is H, hydroxyl or C₁₋₈ alkyl;R¹⁵ is H or C₁₋₈ alkyl;

R¹⁶ is O, S, C(O) or CH₂; and

c is 0 or 1;with the proviso that the compound of Formula I is not of structure

In another aspect, the invention provides a compound having Formula Iwherein “

” represents a double bond “—CR¹⁴═CR¹⁵—”.

In another aspect, the invention provides a compound having Formula Iwherein “

” represents a triple bond “—C≡C—”.

In another aspect, the invention provides a compound having Formula Iwherein L¹ is CH₂.

In another aspect, the invention provides a compound having Formula Iwherein L¹ is O, S or NH.

In another aspect, the invention provides a compound having Formula Iwherein

In another aspect, the invention provides a compound having Formula Iwherein

In another aspect, the invention provides a compound having Formula Iwherein

In another aspect, the invention provides a compound having Formula Iwherein “

” represents a double bond “—CR¹⁴═CR¹⁵—”;

A is C₆ aryl or heterocycle;B is C₆ aryl or heterocycle;R¹ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R² is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R³ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁴ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁵ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁶ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁷ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, C₆ aryl, heterocycle, C₃₋₈cycloakyl or C₃₋₈ cycloalkenyl;R⁸ is halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;

L¹ is CH₂;

R⁹ is H or C₁₋₆ alkyl;

L² is CHR¹⁴;

R¹⁰ is carboxylic acid or PO₃H₂;R¹¹ is H or C₁₋₆ alkyl;a is 0 or 1;b is 1;R¹² is H or C₁₋₆ alkyl;R¹³ is H or C₁₋₆ alkyl;R¹⁴ is H or C₁₋₆ alkyl;R¹⁵ is H or C₁₋₆ alkyl;

R¹⁶ is CH₂; and

c is 0 or 1.

In another aspect, the invention provides a compound having Formula Iwherein “

” represents a double bond “—CR¹⁴═CR¹⁵—”;

A is C₆ aryl or heterocycle;B is C₆ aryl or heterocycle;R¹ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R² is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R³ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁴ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁵ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁶ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁷ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, C₆ aryl, heterocycle, C₃₋₈cycloakyl or C₃₋₈ cycloalkenyl;R⁸ is halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;

L¹ is O, S or NH;

R⁹ is H or C₁₋₆ alkyl;

L² is CHR¹⁴;

R¹⁰ is carboxylic acid or PO₃H₂;R¹¹ is H or C₁₋₆ alkyl;a is 0 or 1;b is 1;R¹² is H or C₁₋₆ alkyl;R¹³ is H or C₁₋₆ alkyl;R¹⁴ is H or C₁₋₆ alkyl;R¹⁵ is H or C₁₋₆ alkyl;

R¹⁶ is CH₂; and

c is 0 or 1.

In another aspect, the invention provides a compound having Formula Iwherein “

” represents a double bond “—CR¹⁴═CR¹⁵—”;

R¹ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R² is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R³ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁴ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁵ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁶ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁷ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, C₆ aryl, heterocycle, C₃₋₈cycloakyl or C₃₋₈ cycloalkenyl;R⁸ is halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;

L¹ is CH₂;

R⁹ is H or C₁₋₆ alkyl;

L² is CHR¹⁴;

R¹⁰ is carboxylic acid or PO₃H₂;R¹¹ is H or C₁₋₆ alkyl;a is 0 or 1;b is 1;R¹² is H or C₁₋₆ alkyl;R¹³ is H or C₁₋₆ alkyl;R¹⁴ is H or C₁₋₆ alkyl;R¹⁵ is H or C₁₋₆ alkyl;

R¹⁶ is CH₂; and

c is 0 or 1.

In another aspect, the invention provides a compound having Formula Iwherein “

” represents a double bond “—CR¹⁴═CR¹⁵—”;

R¹ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R² is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R³ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁴ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁵ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁶ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁷ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, C₆ aryl, heterocycle, C₃₋₈cycloakyl or C₃₋₈ cycloalkenyl;R⁸ is halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;

L¹ is O, NH or S;

R⁹ is H or C₁₋₆ alkyl;

L² is CHR¹⁴;

R¹⁰ is carboxylic acid or PO₃H₂;R¹¹ is H or C₁₋₆ alkyl;a is 0 or 1;b is 1;R¹² is H or C₁₋₆ alkyl;R¹³ is H or C₁₋₆ alkyl;R¹⁴ is H or C₁₋₆ alkyl;R¹⁵ is H or C₁₋₆ alkyl;

R¹⁶ is CH₂; and

c is 0 or 1.

In another aspect, the invention provides a compound having Formula Iwherein “

” represents a triple bond “—C≡C—”;

A is C₆ aryl or heterocycle;B is C₆ aryl or heterocycle;R¹ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R² is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R³ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁴ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁵ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁶ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁷ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, C₆ aryl, heterocycle, C₃₋₈cycloakyl, C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;R⁸ is halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, NR¹²R¹³ or hydroxyl;

L¹ is CH₂; R⁹ is H; L² is CHR¹⁴ or O;

R¹⁰ is carboxylic acid, hydroxyl or PO₃H₂;a is 0 or 1;b is 0 or 1;R¹² is H or C₁₋₆ alkyl;R¹³ is H or C₁₋₆ alkyl;R¹⁴ is H or hydroxyl;

R¹⁶ is O or CH₂; and

c is 0 or 1.

In another aspect, the invention provides a compound having Formula Iwherein “

” represents a triple bond “—C≡C—”;

R¹ is H, halogen, —OC₁₋₆ alkyl or, C₁₋₆ alkyl;R² is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R³ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁴ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁵ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁶ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁷ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, C₆ aryl, heterocycle, C₃₋₈cycloakyl, C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;R⁸ is halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, NR¹²R¹³ or hydroxyl;

L¹ is O, S or NH; R⁹ is H; L² is CHR¹⁴ or O;

R¹⁰ is carboxylic acid, hydroxyl or PO₃H₂;a is 0 or 1;b is 0 or 1;R¹² is H or C₁₋₆ alkyl;R¹³ is H or C₁₋₆ alkyl;R¹⁴ is H or hydroxyl;

R¹⁶ is O or CH₂; and

c is 0 or 1.

In another aspect, the invention provides a compound having Formula Iwherein “

” represents a triple bond “—C≡C—”;

A is C₆ aryl or heterocycle;B is C₆ aryl or heterocycle;R¹ is H, halogen, —OC₁₋₆ alkyl or, C₁₋₆ alkyl;R² is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R³ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁴ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁵ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁶ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁷ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, C₆ aryl, heterocycle, C₃₋₈cycloakyl, C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;R⁸ is halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, NR¹²R¹³ or hydroxyl;

L¹ is O, S or NH; R⁹ is H; L² is CHR¹⁴ or O;

R¹⁰ is carboxylic acid, hydroxyl or PO₃H₂;a is 0 or 1;b is 0 or 1;R¹² is H or C₁₋₆ alkyl;R¹³ is H or C₁₋₆ alkyl;R¹⁴ is H or hydroxyl;

R¹⁶ is O or CH₂; and

c is 0 or 1.

In another aspect, the invention provides a compound having Formula Iwherein “

” represents a triple bond “—C≡C—”;

R¹ is H, halogen, —OC₁₋₆ alkyl or, C₁₋₆ alkyl;R² is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R³ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁴ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁵ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁶ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl;R⁷ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, C₆ aryl, heterocycle, C₃₋₈cycloakyl, C₃₋₈ cycloalkenyl, NR¹²R¹³ or hydroxyl;R⁸ is halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, NR¹²R¹³ or hydroxyl;

L¹ is CH₂; R⁹ is H; L² is CHR¹⁴ or O;

R¹⁰ is carboxylic acid, hydroxyl or PO₃H₂;a is 0 or 1;b is 0 or 1;R¹² is H or C₁₋₆ alkyl;R¹³ is H or C₁₋₆ alkyl;R¹⁴ is H or hydroxyl;

R¹⁶ is O or CH₂; and

c is 0 or 1.

In another aspect, the invention provides a compound having Formula Iwherein “

” represents a triple bond “—C≡C—”;

R¹ is H, fluoro, methyl, methoxy or chloro;R² is H, fluoro, methyl, methoxy or chloro;R³ is H, fluoro, methyl, methoxy or chloro;R⁴ is H, methyl;R⁵ is H, methyl;R⁶ is H, methyl;R⁷ is H, chloro, methyl, bromo, furyl or thienyl;R⁸ is methoxy;

L¹ is CH₂; R⁹ is H; L² is CHR¹⁴ or O;

R¹⁰ is carboxylic acid, hydroxyl or PO₃H₂;a is 0, 1;b is 0 or 1;R¹² is H or C₁₋₆ alkyl;R¹³ is H or C₁₋₆ alkyl;R¹⁴ is H or hydroxyl;

R¹⁶ is O or CH₂; and

c is 0 or 1.

In another embodiment, the invention provides a compound having FormulaI wherein:

“

” represents a triple bond “—C≡C—”;

R¹ is H, fluoro, methyl, methoxy or chloro;R² is H, or chloro;R³ is H or fluoro;R⁴ is H or methyl;R⁵ is H or methyl;

R⁶ is H;

R⁷ is H, chloro, methyl, bromo, furyl or thienyl;R⁸ is methoxy;

L¹ is CH₂; R⁹ is H; L² is CHR¹⁴ or O;

R¹⁰ is carboxylic acid, hydroxyl or PO₃H₂;a is 0 or 1;b is 0 or 1;R¹² is H or C₁₋₆ alkyl;R¹³ is H or C₁₋₆ alkyl;R¹⁴ is H, hydroxyl;

R¹⁶ is O or CH₂; and

c is 0 or 1.

The term “alkyl”, as used herein, refers to saturated, monovalent ordivalent hydrocarbon moieties having linear or branched moieties orcombinations thereof and containing 1 to 8 carbon atoms. One methylene(—CH₂—) group, of the alkyl can be replaced by oxygen, sulfur,sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, or by a divalent C₃₋₈cycloalkyl. Alkyl groups can be substituted by halogen, hydroxyl,cycloalkyl, amino, non-aromatic heterocycles, carboxylic acid,phosphonic acid groups, sulphonic acid groups, phosphoric acid.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms, derived from a saturated cyclichydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic.Cycloalkyl can be substituted by alkyl groups or halogen atoms.

The term “cycloalkenyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms, derived from a saturatedcycloalkyl having one double bond. Cycloalkenyl groups can be monocyclicor polycyclic. Cycloalkenyl groups can be substituted by alkyl groups orhalogen atoms.

The term “halogen”, as used herein, refers to an atom of chlorine,bromine, fluorine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one double bond. C₂₋₆ alkenyl can be in the E orZ configuration. Alkenyl groups can be substituted by alkyl groups.

The term “alkynyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one triple bond.

The term “heterocycle” as used herein, refers to a 3 to 10 memberedring, which can be aromatic or non-aromatic, saturated or non-saturated,containing at least one heteroatom selected form O or N or S orcombinations of at least two thereof, interrupting the carbocyclic ringstructure. The heterocyclic ring can be interrupted by a C═O; the Sheteroatom can be oxidized. Heterocycles can be monocyclic orpolycyclic. Heterocyclic ring moieties can be substituted by hydroxyl,C₁₋₈ alkyl or halogens.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms by removal of one hydrogen. Aryls can be monocyclic or polycyclic.Aryl can be substituted by halogen atoms, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN,C(O)H, C(O)(C₁₋₈ alkyl), NH₂, NH(C₁₋₈ alkyl), N(C₁₋₈ alkyl) (C₁₋₈ alkyl)or hydroxyl. Usually aryl is phenyl. Preferred substitution site on arylare meta and para positions.

The group of formula “—CR¹⁴═CR¹⁵—”, as used herein, represents analkenyl moiety.

The group of formula “—C≡C—”, as used herein, represents an alkynylmoiety.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “carbonyl” as used herein, represents a group of formula“—C(O)”.

The term “carboxyl” as used herein, represents a group of formula“—C(O)O—”.

The term “sulfonyl” as used herein, represents a group of formula“—SO₂”.

The term “sulfate” as used herein, represents a group of formula“—O—S(O)₂—O—”.

The term “carboxylic acid” as used herein, represents a group of formula“—C(O)OH”.

The term “sulfoxide” as used herein, represents a group of formula“—S═O”.

The term “phosphonic acid” as used herein, represents a group of formula“—P(O)(OH)₂”.

The term “phosphoric acid” as used herein, represents a group of formula“—(O)P(O)(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula“—S(O)₂OH”.

The formula “H”, as used herein, represents a hydrogen atom.

The formula “O”, as used herein, represents an oxygen atom.

The formula “N”, as used herein, represents a nitrogen atom.

The formula “S”, as used herein, represents a sulfur atom.

Some compounds of the invention are:

-   [3-({4-[(1E)-4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-en-1-yl]benzyl}amino)propyl]phosphonic    acid;-   3-({4-[(1E)-4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-en-1-yl]benzyl}amino)propanoic    acid;-   3-{2-chloro-4-[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)but-1-yn-1-yl]phenoxy}propane-1,2-diol;-   3-{2-chloro-4-[4-(3,4-dimethylphenyl)-3-(3-methylphenyl)but-1-yn-1-yl]phenoxy}propane-1,2-diol;-   3-{2-chloro-4-[4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-yn-1-yl]phenoxy}propane-1,2-diol;-   3-{4-[3-(3-Chloro-phenyl)-4-(3,4-dimethyl-phenyl)-but-1-ynyl]-3-methyl-benzylamino}-propionic    acid;-   (3-{4-[3-(3-Chloro-phenyl)-4-(3,4-dimethyl-phenyl)-but-1-ynyl]-benzylamino}-propyl)-phosphonic    acid;-   (3-{4-[4-(3,4-Dimethyl-phenyl)-3-(3-methoxy-phenyl)-but-1-ynyl]-benzylamino}-propyl)-phosphonic    acid;-   (3-{4-[4-(3,4-Dimethyl-phenyl)-3-m-tolyl-but-1-ynyl]benzylamino}-propyl)-phosphonic    acid;-   (3-{4-[3-(3-Chloro-phenyl)-4-(3,4-dimethyl-phenyl)-but-1-ynyl]-3-methyl-benzylamino}-propyl)-phosphonic    acid;-   3-({4-[4-(3,4-dimethylphenyl)-3-(3-methoxyphenyl)but-1-yn-1-yl]benzyl}amino)propanoic    acid;-   3-({4-[4-(3,4-dimethylphenyl)-3-(3-methylphenyl)but-1-yn-1-yl]benzyl}amino)propanoic    acid;-   3-({4-[3-(4-chlorophenyl)-4-(3,4-dimethylphenyl)but-1-yn-1-yl]benzyl}amino)propanoic    acid;-   3-({4-[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)but-1-yn-1-yl]benzyl}amino)propanoic    acid;-   3-{[4-(3,4-diphenylbut-1-yn-1-yl)benzyl]amino}propanoic acid;-   [3-({4-[4-(3,4-dimethylphenyl)-3-(3-methylphenyl)but-1-yn-1-yl]-3    methylbenzyl}amino) propyl]phosphonic acid;-   [3-({4-[4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-yn-1-yl]-3-methylbenzyl}amino)    propyl]phosphonic acid;-   [3-({3-bromo-4-[4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-yn-1-yl]benzyl}amino)    propyl]phosphonic acid;-   [3-({4-[4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-yn-1-yl]-3-(2-furyl)benzyl}amino)    propyl]phosphonic acid;-   [3-({4-[4-(3,4-dimethylphenyl)-3-(3-methylphenyl)but-1-yn-1-yl]-3-(2-thienyl)benzyl}amino)    propyl]phosphonic acid;-   [3-({3-bromo-4-[3-(3,5-difluorophenyl)-4-(3,4-dimethylphenyl)but-1-yn-1-yl]benzyl}amino)    propyl]phosphonic acid;-   [3-({4-[4-(3,4-dimethylphenyl)-3-(3-methylphenyl)but-1-yn-1-yl]-3-(2-furyl)benzyl}amino)    propyl]phosphonic acid;-   [3-({4-[4-(3,4-dimethylphenyl)-3-(3-methylphenyl)but-1-yn-1-yl]-2-methylbenzyl}amino)    propyl]phosphonic acid.

Some compounds of Formula I and some of their intermediates have atleast one stereogenic center in their structure. This stereogenic centermay be present in an R or S configuration, said R and S notation is usedin correspondence with the rules described in Pure Appli. Chem. (1976),45, 11-13.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I are able to form.

The acid addition salt form of a compound of Formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid andthe like; or an organic acid such as for example, acetic, hydroxyacetic,propanoic, lactic, pyruvic, malonic, fumaric acid, maleic acid, oxalicacid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoicacid, tannic acid, pamoic acid, citric, methylsulfonic, ethanesulfonic,benzenesulfonic, formic and the like (Handbook of Pharmaceutical Salts,P. Heinrich Stahal& Camille G. Wermuth (Eds), Verlag Helvetica ChemicaActa-Zürich, 2002, 329-345).

Compounds of Formula I and their salts can be in the form of a solvate,which is included within the scope of the present invention. Suchsolvates include for example hydrates, alcoholates and the like.

With respect to the present invention reference to a compound orcompounds, is intended to encompass that compound in each of itspossible isomeric forms and mixtures thereof unless the particularisomeric form is referred to specifically.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

The compounds of the invention are indicated for use in treating orpreventing conditions in which there is likely to be a componentinvolving the sphingosine-1-phosphate receptors.

In another embodiment, there are provided pharmaceutical compositionsincluding at least one compound of the invention in a pharmaceuticallyacceptable carrier.

In a further embodiment of the invention, there are provided methods fortreating disorders associated with modulation of sphingosine-1-phosphatereceptors. Such methods can be performed, for example, by administeringto a subject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one compound of theinvention.

These compounds are useful for the treatment of mammals, includinghumans, with a range of conditions and diseases that are alleviated byS1P modulation.

-   -   Therapeutic utilities of S1P modulators are Ocular Diseases: wet        and dry age-related macular degeneration, diabetic retinopathy,        retinopathy of prematurity, retinal edema, geographic atrophy,        glaucomatous optic neuropathy, chorioretinopathy, hypertensive        retinopathy, ocular ischemic syndrome, prevention of        inflammation-induced fibrosis in the back of the eye, various        ocular inflammatory diseases including uveitis, scleritis,        keratitis, and retinal vasculitis;    -   Systemic vascular barrier related diseases: various inflammatory        diseases, including acute lung injury, its prevention, sepsis,        tumor metastasis, atherosclerosis, pulmonary edemas, and        ventilation-induced lung injury;    -   Autoimmune diseases and immunosuppression: rheumatoid arthritis,        Crohn's disease, Graves' disease, inflammatory bowel disease,        multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative        colitis, antoimmune uveitis, renal ischemia/perfusion injury,        contact hypersensitivity, atopic dermititis, and organ        transplantation;    -   Allergies and other inflammatory diseases: urticaria, bronchial        asthma, and other airway inflammations including pulmonary        emphysema and chronic obstructive pulmonary diseases;    -   Cardiac functions: bradycardia, congestional heart failure,        cardiac arrhythmia, prevention and treatment of atherosclerosis,        and ischemia/reperfusion injury;    -   Wound Healing: scar-free healing of wounds from cosmetic skin        surgery, ocular surgery, GI surgery, general surgery, oral        injuries, various mechanical, heat and burn injuries, prevention        and treatment of photoaging and skin ageing, and prevention of        radiation-induced injuries;    -   Bone formation: treatment of osteoporosis and various bone        fractures including hip and ankles;    -   Anti-nociceptive activity: visceral pain, pain associated with        diabetic neuropathy, rheumatoid arthritis, chronic knee and        joint pain, tendonitis, osteoarthritis, neuropathic pains;    -   Anti-fibrosis: ocular, cardiac, hepatic and pulmonary fibrosis,        proliferative vitreoretinopathy, cicatricial pemphigoid,        surgically induced fibrosis in cornea, conjunctiva and tenon;    -   Pains and anti-inflammation: acute pain, flare-up of chronic        pain, musculo-skeletal pains, visceral pain, pain associated        with diabetic neuropathy, rheumatoid arthritis, chronic knee and        joint pain, tendonitis, osteoarthritis, bursitis, neuropathic        pains;    -   CNS neuronal injuries: Alzheimer's disease, age-related neuronal        injuries;    -   Organ transplants: renal, corneal, cardiac and adipose tissue        transplants.

In still another embodiment of the invention, there are provided methodsfor treating disorders associated with modulation ofsphingosine-1-phosphate receptors. Such methods can be performed, forexample, by administering to a subject in need thereof a therapeuticallyeffective amount of at least one compound of the invention, or anycombination thereof, or pharmaceutically acceptable salts, hydrates,solvates, crystal forms and individual isomers, enantiomers, anddiastereomers thereof.

-   -   The present invention concerns the use of a compound of Formula        I or a pharmaceutically acceptable salt thereof, for the        manufacture of a medicament for the treatment of Ocular        Diseases: wet and dry age-related macular degeneration, diabetic        retinopathy, retinopathy of prematurity, retinal edema,        geographic atrophy, glaucomatous optic neuropathy,        chorioretinopathy, hypertensive retinopathy, ocular ischemic        syndrome, prevention of inflammation-induced fibrosis in the        back of the eye, various ocular inflammatory diseases including        uveitis, scleritis, keratitis, and retinal vasculitis;    -   Systemic vascular barrier related diseases: various inflammatory        diseases, including acute lung injury, its prevention, sepsis,        tumor metastasis, atherosclerosis, pulmonary edemas, and        ventilation-induced lung injury;    -   Autoimmune diseases and immunosuppression: rheumatoid arthritis,        Crohn's disease, Graves' disease, inflammatory bowel disease,        multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative        colitis, antoimmune uveitis, renal ischemia/perfusion injury,        contact hypersensitivity, atopic dermititis, and organ        transplantation;    -   Allergies and other inflammatory diseases: urticaria, bronchial        asthma, and other airway inflammations including pulmonary        emphysema and chronic obstructive pulmonary diseases;    -   Cardiac functions: bradycardia, congestional heart failure,        cardiac arrhythmia, prevention and treatment of atherosclerosis,        and ischemia/reperfusion injury;    -   Wound Healing: scar-free healing of wounds from cosmetic skin        surgery, ocular surgery, GI surgery, general surgery, oral        injuries, various mechanical, heat and burn injuries, prevention        and treatment of photoaging and skin ageing, and prevention of        radiation-induced injuries;    -   Bone formation: treatment of osteoporosis and various bone        fractures including hip and ankles;    -   Anti-nociceptive activity: visceral pain, pain associated with        diabetic neuropathy, rheumatoid arthritis, chronic knee and        joint pain, tendonitis, osteoarthritis, neuropathic pains;    -   Anti-fibrosis: ocular, cardiac, hepatic and pulmonary fibrosis,        proliferative vitreoretinopathy, cicatricial pemphigoid,        surgically induced fibrosis in cornea, conjunctiva and tenon;    -   Pains and anti-inflammation: acute pain, flare-up of chronic        pain, musculo-skeletal pains, visceral pain, pain associated        with diabetic neuropathy, rheumatoid arthritis, chronic knee and        joint pain, tendonitis, osteoarthritis, bursitis, neuropathic        pains;    -   CNS neuronal injuries: Alzheimer's disease, age-related neuronal        injuries;    -   Organ transplants: renal, corneal, cardiac and adipose tissue        transplants.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back to the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventioncompounds are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or diseasecondition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Invention compounds may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein areuseful as medicaments in mammals, including humans, for treatment ofdiseases and/or alleviations of conditions which are responsive totreatment by agonists or functional antagonists ofsphingosine-1-phosphate receptors. Thus, in further embodiments of theinvention, there are provided methods for treating a disorder associatedwith modulation of sphingosine-1-phosphate receptors. Such methods canbe performed, for example, by administering to a subject in need thereofa pharmaceutical composition containing a therapeutically effectiveamount of at least one invention compound. As used herein, the term“therapeutically effective amount” means the amount of thepharmaceutical composition that will elicit the biological or medicalresponse of a subject in need thereof that is being sought by theresearcher, veterinarian, medical doctor or other clinician. In someembodiments, the subject in need thereof is a mammal. In someembodiments, the mammal is human.

The synthetic schemes set forth below, illustrate how compoundsaccording to the invention can be made. Those skilled in the art will beable to routinely modify and/or adapt the following scheme to synthesizeany compounds of the invention covered by Formula I.

The following abbreviations are used in the general schemes and in thespecific examples:THF tetrahydrofuranMPLC medium pressure liquid chromatography

NMO 4-Methylmorpholine N-oxide

CH₃CN acetonitrileCH₂Cl₂ dichloromethaneTPAP Tetrapropylammonium perruthenateMeOH methanolNaCNBH₃ sodium cyanoborohydrideCD₃OD deuterated methanolDMSO-d6 deuterated dimethyl sulfoxideNaOMe sodium methoxydeEtOH ethanolNaBH₄ sodium borohydrideMgSO₄ magnesium sulfateNH₄Cl ammonium chlorideHCl hydrochloric acidDIBAL-H Diisobutylaluminium hydrideEt₂O etherMeOH methanolK₂CO₃ potassium carbonate

DMF N,N-dimethylformamide

Et₃N triethylamineCuI cooper iodidePdCl₂(PPh₃)₂ Bis(triphenylphosphine)palladium(II) chlorideNaH sodium hydrideEtOAc ethylacetateAcOH acetic acidTFA trifluoroacetic acidNH₃ ammoniaCDCl₃ deuterated chloroform

General Synthetic Methods

Reaction Schemes A, B, C, D and E are examples of general methods forobtaining the compounds disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand racemic mixtures. Some of the compounds of the invention may formsalts with pharmaceutically acceptable acids or bases, and suchpharmaceutically acceptable salts of the compounds described herein arealso within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of protium ¹H (or H)or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

As will be evident to those skilled in the art, individual isomericforms can be obtained by separation of mixtures thereof in conventionalmanner. For example, in the case of diasteroisomeric isomers,chromatographic separation may be employed.

Compound names were generated with ACD version 8, intermediates' andreagents' names used in the examples were generated with software suchas Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 from MDL ISIS Draw2.5 SP1.

In general, characterization of the compounds is performed using NMRspectra, which were recorded on 300 and/or 600 MHz Varian and acquiredat room temperature. Chemical shifts are given in ppm referenced eitherto internal TMS or to the solvent signal.

All the reagents, solvents, catalysts for which the synthesis is notdescribed are purchased from chemical vendors such as Sigma Aldrich,Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, TransWorld Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth,Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex,MIC-scientific, Ltd; however some known intermediates, were preparedaccording to published procedures.

Usually the compounds of the invention were purified by columnchromatography (Auto-column) on an Teledyne-ISCO CombiFlash with asilica column, unless noted otherwise.

The present invention concerns also processes for preparing thecompounds of Formula I. The compounds of Formula I according to theinvention can be prepared analogously to conventional methods asunderstood by the person skilled in the art of synthetic organicchemistry.

Example 1 Intermediate 13-(3,4-dimethylphenyl)-2-(3-methoxyphenyl)propanal

To a solution of 3,4-dimethylbenzaldehyde (CAS 68844-97-3) (4.0 g, 29.6mmol) and 3-methoxybenzyl)acetonitrile (CAS 19924-43-7) (4.35 g, 29.6mmol) in absolute EtOH, 30 mL, was added NaOMe (0.1 equiv), the mixturewas stirred at room temperature for 2 h. Then, the reaction mixture wascooled to 0° C. and filtered. The precipitate was washed with cold EtOHand gave (2E)-3-(3,4-dimethylphenyl)-2-(3-methoxyphenyl)acrylonitrile asa white solid (6.20 g, 78%).

NaBH₄ (1.8 g, 47 mmol) was added slowly to the solution of(2E)-3-(3,4-dimethylphenyl)-2-(3-methoxyphenyl)acrylonitrile (6.17 g,23.5 mmol) in EtOH (100 mL) under argon. The mixture was stirred at 70°C. for 16 h. The solution was cooled to room temperature and quenchedwith water. The reaction mixture was diluted with 100 mL water andacidified with 6M HCl (aq.). After extraction with ether (3×100 mL), thecombined organic layers were washed with water and brine, dried overMgSO₄, filtered and concentrated to get3-(3,4-dimethylphenyl)-2-(3-methoxyphenyl)propanenitrile as a whitesolid (6 g, 96%).

DIBAL-H (1.0 M in toluene, 14 mL, 14 mmol) was added dropwise to thesolution of 3-(3,4-dimethylphenyl)-2-(3-methoxyphenyl)propanenitrile(2.93 g, 11.72 mmol) in Toluene (40 mL) at −78° C. under argon. Themixture was stirred at −78° C. to −20° C. for 3 h and then quenched byslow addition of saturated NH₄Cl solution (2 mL) followed by Celite (2g) at −20° C. The mixture was diluted with Et₂O (50 mL), warmed slowlyto room temperature, and stirred till all aluminum precipitated. Thesolid was filtered and washed with ether (3×50 mL), the combined organiclayers wer dried over MgSO₄, filtered and concentrated and gaveIntermediate 1 (2.34 g, 74%).

¹H NMR (CDCl₃, 300 MHz) δ: 9.72 (d, J=1.8 Hz, 1H), 7.21-7.34 (m, 1H),6.98 (d, J=7.3 Hz, 1H), 6.74-6.92 (m, 4H), 6.70 (s, 1H), 3.69-3.89 (m,4H), 3.40 (dd, J=14.1, 7.3 Hz, 1H), 2.92 (dd, J=14.1, 7.3 Hz, 1H), 2.20(d, 6H).

Intermediate 2 was prepared in a similar manner to the proceduredescribed in Example 1 for Intermediate 1. The starting materials andthe results are tabulated below in Table 1.

TABLE 1 Interm. ¹NMR num- Starting (Solvent; δ ber Intermediate namematerial ppm) 2

3,4-dimethyl benzaldehyde (CAS 68844-97-3) 3-fluoro- benzene-acetonitrile (CAS 501-00-8) ¹H NMR (CDCl₃, 300 MHz) δ: 9.72 (d, J = 1.5Hz, 1H), 9.68-9.75 (m, 1H), 7.22-7.36 (m, 1H), 6.83-7.03 (m, 3H), 6.78(d, J = 7.6 Hz, 1H), 3.76-3.87 (m, 1H), 3.38 (dd, J = 14.1, 7.0 Hz, 1H),2.90 (dd, J = 14.1, 7.9 Hz, 1H), 2.18 (d, 6H)

Example 2 Intermediate 34-[2-(3-methoxyphenyl)but-3-yn-1-yl]-1,2-dimethylbenzene

To a solution of Intermediate 1 (2.34 g, 8.7 mmol) in MeOH (40 ml) wasadded dimethyl (1-diazo-2-oxopropyl)phosphonate (CAS 90965-06-3) (2.01 g10.4 mmol) at 0° C. followed by K₂CO₃ (2.4 g, 17.4 mmol). The reactionmixture was stirred at room temperature for 16 hours. The reactionmixture was quenched with water and extracted with CH₂Cl₂ (3×50 mL), thecombined organic layers were dried over MgSO₄, filtered andconcentrated. The crude product was purified on a column (MPLC) usinghexane:ethyl acetate to give Intermediate 3 (1 g).

¹H NMR (CDCl₃, 300 MHz) δ 7.18-7.29 (m, 1H), 7.03 (d, J=7.6 Hz, 1H),6.87-6.96 (m, 4H), 6.79 (dd, J=8.2, 2.3 Hz, 1H), 3.73-3.88 (m, 4H), 2.97(d, J=7.6 Hz, 2H), 2.23 (s, 6H).

Example 3 Intermediate 44-[4-(3,4-dimethylphenyl)-3-(3-methoxyphenyl)but-1-yn-1-yl]benzaldehyde

To a solution of Intermediate 3 (573 mg, 2.17 mmol) in anhydrous DMF (10mL), 4-iodobenzaldehyde (553 mg, 2.38 mmol) followed by Et₃N (0.9 mL,6.51 mmol) and CuI (83 mg, 0.434 mmol). The reaction mixture was bubbledwith argon, followed by the addition of PdCl₂(PPh₃)₂ (114 mg, 0.163mmol) under argon. The reaction solution was stirred at room temperaturefor 16 h. The reaction mixture was quenched with water and extractedwith EtOAc (3×50 mL), the combined organic layers were dried over MgSO₄,filtered and concentrated. The crude product was purified on a column(MPLC) using hexane:ethyl acetate to get Intermediate 4 (535 mg).

¹NMR (CDCl₃, 300 MHz) δ: 9.97 (s, 1H), 7.79 (d, J=8.2 Hz, 2H), 7.51 (d,J=8.2 Hz, 2H), 7.18-7.32 (m, 1H), 6.88-7.08 (m, 5H), 6.81 (dd, J=8.4,2.2 Hz, 1H), 4.04 (t, J=7.3 Hz, 1H), 3.80 (s, 3H), 3.05 (d, J=6.7 Hz,2H), 2.24 (s, 6H).

Intermediate 5 was prepared in a similar manner to the proceduredescribed in Example 3 for Intermediate 4. The starting materials andthe results are tabulated below in Table 2 for each case.

TABLE 2 Interm. ¹NMR (Solvent; δ number Intermediate name Startingmaterial ppm) 5

3,4- dimethylbenzaldehyde (CAS 68844-97-3) Benzeneacetonitrile, 3-chloro- (CAS 1529-41-5) ¹H NMR (CDCl₃, 300 MHz) δ: 9.99 (s, 1H),7.77-7.88 (m, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.39-7.46 (m, 1H), 7.37 (s,1H), 7.16-7.31 (m, 2H), 6.85-7.08 (m, 3H), 4.04 (t, J = 7.2 Hz, 1H),3.04 (d, J = 7.3 Hz, 2H), 2.24 (d, J = 2.6 Hz, 6H)

Example 4 Intermediate 6{4-[(1E)-4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-en-1-yl]phenyl}methanol

A solution of methyl 4-[dimethoxyphosphoryl)methyl]benzoate (CAS78022-19-2) (2.61 g, 9.14 mmol) in THF 10 (mL) was added to a suspensionof NaH (366 mg) in THF (20 mL) at 0° C. and the mixture was stirred at0° C. for 20 minutes. After 20 minutes a solution of Intermediate 2 (1.8g, 7.03 mmol) in THF (10 mL) was added to the reaction mixture at 0° C.and stirred at 0° C. for another 2 h. The reaction mixture was quenchedwith saturated NH₄Cl and extracted with ether (3×100 mL), the combinedorganic layers were dried over MgSO₄, filtered and concentrated to givemethyl4-[(1E)-4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-en-1-yl]benzoate(2.7 M.

DIBAL-H (1.5 M in toluene, 14 mL, 20.85 mmol) was added dropwise to asolution of4-[(1E)-4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-en-1-yl]benzoate(2.7 g, 6.95 mmol) in THF (60 mL) at −78° C. under argon. The mixturewas stirred at −78° C. to room temperature for 3 h. The mixture wascooled to −20° C. and then quenched by slow addition of saturated NH₄Clsolution (4 mL) followed by Celite (4 g) at −20° C. The mixture wasdiluted with Et₂O (50 mL), warmed slowly to room temperature, andstirred till all aluminum precipitated. The solid was filtered andwashed with ether (3×50 mL), and combined organic layer was dried overMgSO₄, filtered, concentrated and gave Intermediate 6 (1.3 g).

¹H NMR (CDCl₃, 300 MHz) δ: 7.19-7.33 (m, 6H), 6.75-7.01 (m, 5H),6.23-6.42 (m, 2H), 4.65 (s, 2H), 3.71 (q, J=7.2 Hz, 1H), 3.02 (dd,J=7.5, 3.1 Hz, 2H), 2.19 (d, J=2.9 Hz, 6H).

Example 5 Intermediate 74-[(1E)-4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-en-1-yl]benzaldehyde

To a solution of Intermediate 6 (1.3 g, 3.6 mmol) in anhydrous CH₂Cl₂(20 mL) and CH₃CN (2 mL), was added molecular sieves (500 mg), NMO (845mg, 7.2 mmol) and TPAP (50 mg) at room temperature. The reaction mixturewas stirred at room temperature for 2 h and then was passed through asmall pad of silicagel column chromatography and eluted in 50% EtOAc inhexane and afforded Intermediate 7 (1.07 g).

¹H NMR (CDCl₃, 300 MHz) δ: 9.95 (s, 1H), 7.79 (d, J=8.2 Hz, 2H), 7.43(d, J=8.2 Hz, 2H), 6.76-7.03 (m, 7H), 6.24-6.59 (m, 2H), 3.63-3.79 (m,1H), 3.05 (d, J=7.3 Hz, 2H), 2.19 (d, J=3.2 Hz, 6H).

Example 6 Intermediate 8(3-bromo-4-(4-(3,4-dimethylphenyl)-3-(m-tolyl)but-1-yn-1-yl)phenyl)methanol

A solution of (3-bromo-4-iodophenyl)methanol (CAS 249647-26-5) (1.95 g,6.23 mmole, 0.9 eq) and 1,2-dimethyl-4-(2-(m-tolyl)but-3-yn-1-yl)benzene(obtained according to the procedure of Example 3, from3,4-dimethylbenzaldehyde (CAS 68844-97-3) (4.0 g, 29.6 mmol) and3-methylbenzyl)acetonitrile (CAS 620-22-4) (1.72 g, 6.9 mmole, 1.0 eq)in THF was cooled to 0° C. Triethylamine (1.93 mL, 2.0 eq) and CuI (263mg, 0.2 eq) were added and argon was bubbled into the resulting mixturefor 5 minutes. Dichlorobis(triphenylphosphine)palladium (II) (486 mg,0.1 eq) was added and Argon was bubbled into the resulting mixture for 5minutes. The reaction was stirred at 0° C. for 6 hours after which itwas concentrated under reduced pressure. Purification by MPLC afforded1.7 g of Intermediate 8.

Example 7 Intermediate 9(4-(4-(3,4-dimethylphenyl)-3-(m-tolyl)but-1-yn-1-yl)-3-(thiophen-2-yl)phenyl)methanol

To a solution of Intermediate 8 (840 mg, 1.0 eq) andtributyl(thiophen-2-yl)stannane (1.4 g, 2.0 eq) in DMF in a microwavevial was added dichlorobis(triphenylphosphine)palladium (II) (204 mg,0.15 eq). Argon was bubbled into the reaction mixture for 5 minutes. Thevial was capped and microwaved at 160° C. for 20 minutes. The reactionmixture was concentrated under reduced pressure and purified by MPLC togive 480 mg of Intermediate 9.

Example 8 Intermediate 104-(4-(3,4-dimethylphenyl)-3-(m-tolyl)but-1-yn-1-yl)-3-(thiophen-2-yl)benzaldehyde

To a solution of 480 mg of Intermediate 9 in CH₂Cl₂ (20 mL) and CH₃CN (2mL) were added 150 mg of molecular sieves. The resulting mixture wasstirred for 5 minutes after which 260 mg of N-Methylmorpholine oxide(2.0 eq) was added followed by 25 mg of TPAP. The resulting mixture wasstirred at room temperature for 2 hours. It was then filtered through alayer of SiO₂. The filtrate was concentrated and purified by MPLC togive 255 mg of Intermediate 10.

Example 9 Intermediate 11(4-(4-(3,4-dimethylphenyl)-3-(m-tolyl)but-1-yn-1-yl)-3-(furan-2-yl)phenyl)methanol

To a solution of Intermediate 8 (860 mg, 1.0 eq) andtributyl(furan-2-yl)stannane (1.4 g, 2.0 eq) in DMF in a microwave vialwas added dichlorobis(triphenylphosphine)palladium (II) (208 mg, 0.15eq). Argon was bubbled into the reaction mixture for 5 minutes. The vialwas capped and microwaved at 160° C. for 20 minutes. The reactionmixture was concentrated under reduced pressure and purified by MPLC togive 530 mg of Intermediate 11.

Example 10 Intermediate 124-(4-(3,4-dimethylphenyl)-3-(m-tolyl)but-1-yn-1-yl)-3-(furan-2-yl)benzaldehyde

To a solution of 530 mg of Intermediate 11 in CH₂Cl₂ (20 mL) and CH₃CN(2 mL) were added 200 mg of molecular sieves. The resulting mixture wasstirred for 5 minutes after which 295 mg of N-Methylmorpholine oxide(2.0 eq) was added followed by 30 mg of TPAP. The resulting mixture wasstirred at room temperature for 2 hours. It was then filtered through alayer of SiO₂. The filtrate was concentrated and purified by MPLC togive Intermediate 12.

Example 11 Intermediate 13 3-(4-bromo-2chlorophenoxy)propane-1,2-diol

To a solution of 4-bromo-2-chlorophenol (5.0 g, 24.1 mmol, CAS3964-56-5), in ethanol (14 ml) was added NaOH (1.20 g, 30.1 mmol) andthe solution was refluxed for 10 mins. The reaction was cooled and3-chloropropane-1,2-diol (3.2 g, 28.9 mmol, CAS 96-24-2) in ethanol (10mL) was added and the reaction was refluxed for 5 hours. The reactionwas cooled to room temperature and ethanol was removed under reducedpressure. The residue was diluted with ether and washed with water andextracted with ether. The organic phase was washed with brine and driedover MgSO₄ and the crude product was purified on a column (MPLC) usingCH₂Cl₂:MeOH and gave Intermediate 13 (4.6 g). ¹H-NMR (CDCl₃, 300 MHz)δ=7.81 (s, 1H), 7.42 (d, J=8.7 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H),4.62-4.70 (m, 2H), 3.42-3.98 (m, 3H).

Example 12 Compound 13-({4-[4-(3,4-dimethylphenyl)-3-(3-methoxyphenyl)but-1-yn-1-yl]benzyl}amino)propanoicacid

3-aminopropanoic acid (CAS 107-95-9) (32 mg, 0.35 mmol) was added to asolution of Intermediate 4 (86 mg, 0.233 mmol) in MeOH (5 mL) followedby AcOH (2 drops) at room temperature. The reaction mixture was stirredat room temperature for 20 minutes then NaCNBH₃ (15 mg, 0.233 mmol) wasadded to the reaction mixture in 2 mL MeOH. The reaction mixture wasstirred at room temperature for 2 h. The reaction mixture was thenquenched with water (1 mL) and celite was added concentrated to dryness,purified by reverse phase MPLC using CH₃CN:H₂O and gave Compound 1 (62mg).

¹H NMR (CD₃OD, 300 MHz) δ: 7.36-7.45 (m, 4H), 7.18-7.27 (m, 1H),6.92-7.02 (m, 3H), 6.83-6.87 (m, 2H), 6.76-6.83 (m, 1H), 4.18 (s, 2H),4.02-4.09 (m, 1H), 3.75 (s, 3H), 3.15 (t, J=6.4 Hz, 2H), 2.95-3.04 (m,2H), 2.49 (t, J=6.3 Hz, 2H).

Compound 2 was prepared in a similar manner to the procedure describedin Example 12 for Compound 1. The starting materials and the results aretabulated below in Table 3.

TABLE 3 Comp. ¹NMR (Solvent; δ number IUPAC name Starting material ppm)2

3,4-dimethyl benzaldehyde (CAS 68844-97-3) Benzeneacetonitrile 3-chloro- (CAS 1529-41-5) Benzaldehyde, 4- iodo-3-methyl- (CAS1160925-07-1) ¹H NMR (CD₃OD, 300 MHz) δ: 7.38 (d, J = 7.9 Hz, 2H), 7.30(d, J = 5.9 Hz, 3H), 7.20-7.28 (m, 2H), 6.94-7.02 (m, 2H), 6.84-6.92 (m,1H), 4.20 (dd, J = 8.1, 6.3 Hz, 1H), 4.14 (s, 2H), 3.15 (t, J = 6.3 Hz,2H), 2.90-3.10 (m, 2H), 2.48 (t, J = 6.4 Hz, 2H), 2.32 (s, 3H), 2.19 (d,6H)

Example 13 Compound 33-({4-[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)but-1-yn-1-yl]benzyl}amino)propanoicacid

3-aminopropanoic acid (150 mg, 0.825 mmol) was added to a solution ofIntermediate 5, (210 mg, 0.55 mmol) in MeOH (10 mL) followed by Et₃N(0.107 mL, 0.77 mmol) at room temperature. The reaction mixture wasstirred at 50° C. for 30 minutes then the mixture was cooled to 0° C.and NaBH₄ (21 mg, 0.55 mmol) was added to the reaction mixture in 2 mLMeOH. The reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was then quenched with water (0.5 mL) and silica gelwas added, concentrated to dryness, then purified by MPLC usingMeOH:CH₂Cl₂ gave (188 mg) of tert-butyl3-((4-[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)but-1-yn-1-yl)benzyl)amino)propanoate.

¹H NMR (CDCl₃, 300 MHz) δ: 7.37 7.33 (m, 3H), 7.20-7.29 (m, 4H),6.84-7.08 (m, 4H), 3.99 (t, J=7.2 Hz, 1H), 3.78 (s, 2H), 3.01 (d, J=7.3Hz, 2H), 2.83 (t, J=6.3 Hz, 2H), 2.44 (t, J=6.4 Hz, 2H), 2.23 (s, 6H),1.44 (s, 9H).

To a solution of tert-butyl3-((4-[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)but-1-yn-1-yl)benzyl)amino)propanoatein CH₂Cl₂ (10 mL) was added TFA (1 mL) at room temperature and themixture was stirred at room temperature for 16 h. The mixture wasevaporated under reduced pressure. The residue was diluted withCH₂Cl₂:MeOH and the mixture was neutralized with NH₃:MeOH silica gel wasadded, concentrated to dryness, then purified by MPLC using MeOH:CH₂Cl₂and Compound 3 (129 mg).

¹H NMR (CD₃OD, 300 MHz) δ: 7.44 (s, 4H), 7.34 (s, 1H), 7.24-7.31 (m,3H), 6.83-7.03 (m, 3H), 4.20 (s, 2H), 4.06-4.17 (m, 1H), 3.18 (t, J=6.4Hz, 2H), 2.93-3.08 (m, 2H), 2.53 (t, J=6.3 Hz, 2H), 2.21 (d, J=4.1 Hz,6H).

Compounds 4 through 6 were prepared in a similar manner to the methoddescribed in Example 13 for Compound 3. The starting materials and theresults are tabulated below in Table 4 for each case.

TABLE 4 Comp. ¹NMR (Solvent; δ number IUPAC name Starting material ppm)4

3,4-dimethyl benzaldehyde (CAS 68844-97-3) Benzene acetonitrile, 3-methyl- (CAS 2947-60-6) ¹H NMR (CD₃OD, 300 MHz) δ: 7.42 (s, 4H),7.10-7.23 (m, 3H), 7.05 (d, J = 6.7 Hz, 1H), 6.93-7.02 (m, 2H),6.84-6.91 (m, 1H), 4.19 (s, 2H), 4.02 (dd, J = 8.4, 6.3 Hz, 1H), 3.18(t, J = 6.4 Hz, 2H), 2.88-3.06 (m, 2H), 2.54 (t, J = 6.4 Hz, 2H), 2.32(s, 3H), 2.20 (d, 6H) 5

3,4-dimethyl benzaldehyde (CAS 68844-97-3) Benzene acetonitrile, 4-chloro- (CAS 140-53-4) ¹H NMR (CD₃OD, 300 MHz) δ: 7.44 (s, 4H), 7.30 (d,J = 1.8 Hz, 4H), 6.91-7.03 (m, 2H), 6.85 (d, J = 7.6 Hz, 1H), 4.23 (s,2H), 4.05-4.15 (m, 1H), 3.28 (t, J = 6.7 Hz, 2H), 2.95-3.05 (m, 2H),2.75 (t, J = 6.7 Hz, 2H), 2.20 (d, J = 3.8 Hz, 6H) 6

Benzene acetonitrile (CAS 140-29-4) Benzaldehyde (CAS 100-52-7) ¹H NMR(CD₃OD, 300 MHz) δ: 7.42 (s, 4H), 7.14-7.38 (m, 8H), 4.19 (s, 2H),4.08-4.17 (m, 1H), 3.04-3.19 (m, 4H), 2.50 (t, 2H)

Example 14 Compound 7(3-{4-[4-(3,4-Dimethyl-phenyl)-3-(3-methoxy-phenyl)-but-1-ynyl]-benzylamino}-propyl)-phosphonicacid

Intermediate 4 (96 mgs, 0.26 mmol) was dissolved in Methanol (8 mL) at50° C. (3-aminopropyl)phosphonic acid (CAS 13138-33-5) (36 mgs, 0.26mmol) was added followed by tert-butyl ammonium hydroxide (0.26 ml, 1.0M in MeOH). The reaction mixture was stirred at 30 minutes until itbecame a clear solution. Sodium cyano borohydride (10 mgs, 0.26 mmol)was added and the reaction was stirred at 50° C. for 3 hours, thereaction mixture was cooled to room temperature and silica gel was addedconcentrated to dryness, then purified on a column (MPLC) usingCH₂Cl₂:MeOH and gave Compound 7 (52 mg).

¹H NMR (CD₃OD, 300 MHz) δ 7.32-7.49 (m, 4H), 7.20 (t, J=7.9 Hz, 1H),6.91-7.02 (m, 3H), 6.87 (br. s., 2H), 6.72-6.82 (m, 1H), 4.02 (s, 3H),3.73 (s, 3H), 2.89-3.05 (m, 4H), 1.82-2.02 (m, 2H), 1.53-1.71 (m, 2H).

Compounds 8 through 18 were prepared in a similar manner to the methoddescribed in Example 14 for Compound 7. The starting materials and theresults are tabulated below in Table 5 for each case.

TABLE 5 Comp. ¹NMR (Solvent; number IUPAC name Starting material δ ppm) 8

3,4-dimethyl benzaldehyde (CAS 68844-97-3) Benzene acetonitrile, 4-chloro- (CAS 140-53-4) ¹H NMR (CD₃OD, 300 MHz) δ: 7.24- 7.49 (m, 8H),6.84-6.99 (m, 3H), 4.07 (t, J = 7.2 Hz, 1H), 4.02 (s, 2H), 2.96-3.00 (m,4H), 2.02 (s, 3H), 2.19 (s, 3H), 1.96-1.88 (m, 2H), 1.60- 1.70 (m, 2H). 9

3,4-dimethyl benzaldehyde (CAS 68844-97-3) Benzene acetonitrile, 3-methyl- (CAS 2947-60-6) ¹H NMR (CD₃OD, 300 MHz) δ: 7.25- 7.57 (m, 2H),7.04-7.28 (m, 2H), 6.81-7.04 (m, 2H), 4.05 (s, 2H), 3.19-3.34 (m, 4H),3.17- 3.25 (m, 1H), 2.87-3.08 (m, 2H), 2.31 (s, 2H), 2.20-2.24 (m, 2H),2.19 (br. s., 2H), 1.35- 2.04 (m, 4H), 1.13-1.35 (m, 1H), 0.90-1.13 (m,1H) 10

3,4-dimethyl benzaldehyde (CAS 68844-97-3) Benzene acetonitrile, 3-chloro- (CAS 1529-41-5) Benzaldehyde, 4- iodo-3-methyl- (CAS1160924-07- 1) ¹H NMR (CD₃OD, 300 MHz) δ: (m, 7H), 6.97 (d, J = 7.2 Hz,1H), 6.887 (d, J = 7.2 Hz, 1H), 6.940 (s, 1H), 4.186 (J = 8.1 Hz, 1H),4.00 (s, 2H), 2.96-3.04 (m, 4H), 2.30 (s, 3H), 2.20 (s, 3H), 2.19 (s,3H), 1.91-1.97 (m, 2H), 1.60- 1.70 (m, 2H). 11

Benzaldehyde, 4- iodo-3-methyl- (CAS 1160924- 07-1) 3,4-dimethylbenzaldehyde (CAS 68844-97-3) Benzeneacetonitrile, 3-methyl-(CAS 2947-60-6) ¹H NMR (CD₃OD, 300 MHz) δ: 7.29- 7.36 (m, 2H), 7.14-7.26(m, 4H), 7.05 (d, J = 5.9 Hz, 1H), 6.93-7.01 (m, 2H), 6.86-6.93 (m, 1H),4.04- 4.15 (m, 1H), 4.03 (s, 2H), 2.91-3.09 (m, 4H), 2.31 (d, J = 6.4Hz, 6H), 2.20 (d, J = 5.0 Hz, 6H), 1.87- 2.02 (m, 2H), 1.57-1.76 (m, 2H)12

Benzaldehyde, 4- iodo-3-methyl- (CAS 1160924-07-1) 3,4-dimethylbenzaldehyde (CAS 68844-97-3) Benzeneacetonitrile, 3-fluoro- (CAS501-00-8) ¹H NMR (DMSO-d⁶, 300 MHz) δ: 7.30- 7.43 (m, 2H), 7.15-7.30 (m,4H), 6.88-7.13 (m, 4H), 4.22- 4.33 (m, 1H), 3.75 (br. s., 2H), 2.97-3.08(m, 1H), 2.83-2.97 (m, 1H), 2.60- 2.74 (m, 2H), 2.21 (s, 3H), 2.13 (s,6H), 1.65-1.79 (m, 2H), 1.47-1.65 (m, 2H). 13

3,4- dimethylbenzaldehyde (CAS 68844-97-3) Benzene acetonitrile,3-fluoro- (CAS 501-00-8) Benzaldehyde, 3- bromo-4-iodo- (CAS873387-82-7) ¹H NMR (DMSO-d⁶, 300 MHz) δ: 7.76 (s, 1H), 7.19-7.45 (m,5H), 6.84- 7.12 (m, 4H), 4.28 (dd, J = 8.8, 6.2 Hz, 1H), 3.82 (s, 2H),2.86-3.07 (m, 2H), 2.69 (br. s., 2H), 2.13 (s, 6H), 1.63- 1.83 (m, 2H),1.46-1.63 (m, 2H). 14

3,4- dimethylbenzaldehyde (CAS 68844-97-3) Benzeneacetonitrile,3-fluoro- (CAS 501-00-8) ¹H NMR (CD₃OD, 300 MHz) δ: 8.32 (s, 1H), 8.01(d, J = 8.5 Hz, 1H), 7.80 (d, J = 2.1 Hz, 1H), 7.72 (s, 1H), 7.59 (d, J= 7.3 Hz, 1H), 7.19 (td, J = 8.0, 6.0 Hz, 2H), 7.05 (d, J = 7.9 Hz, 1H),6.68-7.01 (m, 5H), 4.69 (t, J = 7.8 Hz, 1H), 4.27 (s, 2H), 3.46-3.57 (m,1H), 3.33-3.44 (m, 1H), 3.03- 3.12 (m, 2H), 2.11 (d, J = 5.9 Hz, 6H),1.85- 2.04 (m, 2H), 1.54-1.76 (m, 2H) 15

3,4-dimethyl benzaldehyde (CAS 68844-97-3) Benzeneacetonitrile,3-methyl- (CAS 2947-60-6) ¹H NMR (DMSO-d⁶, 300 MHz) δ: 7.57 (s, 1H),7.51 (d, J = 5.0 Hz, 1H), 7.40-7.47 (m, 1H), 7.24-7.36 (m, 2H), 7.13-7.24 (m, 2H), 6.93-7.07 (m, 4H), 6.81-6.93 (m, 2H), 4.13 (dd, J = 8.9,6.0 Hz, 1H), 3.74 (s, 2H), 3.14 (d, J = 17.0 Hz, 2H), 2.85-3.02 (m, 2H),2.52- 2.63 (m, 2H), 2.26 (s, 3H), 2.12 (d, J = 5.0 Hz, 6H), 1.44- 1.60(m, 2H). 16

Benzaldehyde, 3- bromo-4-iodo- (CAS 873387-82-7) 3,4-dimethylbenzaldehyde (CAS 68844-97-3) Benzeneacetonitrile, 3,5-difluoro (CAS122376-76-5) ¹H NMR (DMSO-d⁶, 300 MHz) δ: 7.66 (s, 1H), 7.25-7.40 (m,2H), 6.83- 7.15 (m, 6H), 3.78-3.85 (m, 1H), 3.72 (s, 2H), 3.08-3.20 (m,2H), 2.52- 2.65 (m, 2H), 2.02-2.16 (m, 8H), 1.47-1.60 (m, 2H). 17

3,4-dimethyl benzaldehyde (CAS 68844-97-3) Benzeneacetonitrile,3-methyl- (CAS 2947-60-6) ¹H NMR (DMSO-d⁶, 300 MHz) δ: 7.81 (s, 1H),7.71 (d, J = 1.2 Hz, 1H), 7.37 (s, 2H), 7.17-7.30 (m, 3H), 7.03-7.10 (m,2H), 6.98 (d, J = 3.5 Hz, 2H), 6.80-6.90 (m, 1H), 6.30- 6.43 (m, 1H),4.26 (dd, J = 9.1, 5.9 Hz, 1H), 3.92 (s, 2H), 2.88-3.10 (m, 2H), 2.79(d, J = 5.0 Hz, 2H), 2.29 (s, 3H), 2.14 (d, J = 5.3 Hz, 6H), 1.65-1.85(m, 2H), 1.36-1.50 (m, 2H) 18

Benzene acetonitrile, 3- methyl- (CAS 947-60-6) 3,4-dimethylbenzaldehyde (CAS 68844-97-3) Benzaldehyde, 4- iodo-3-methyl- (CAS1160924-07-1) ¹H NMR (DMSO-d⁶, 300 MHz) δ: 7.38 (d, J = 7.6 Hz, 1H),7.11-7.25 (m, 5H), 6.88-7.10 (m, 4H), 4.07 (dd, J = 8.8, 5.6 Hz, 1H),3.85 (s, 2H), 2.78- 3.04 (m, 4H), 2.29 (d, J = 3.5 Hz, 6H), 2.16 (d, J =3.2 Hz, 6H), 1.66-1.89 (m, 2H), 1.49- 1.61 (m, 2H).

Example 15 Compound 193-{2-chloro-4-[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)but-1-yn-1-yl]phenoxy}propane-1,2-diol

To a solution of 4-(2-(3-chlorophenyl)but-3-yn-1-yl)-1,2-dimethylbenzene(396 mg, 1.47 mmol), prepared from 3,4-dimethylbenzaldehyde (CAS68844-97-3) and Benzeneacetonitrile, 3-chloro- (CAS 1529-41-5) accordingto the procedure for Intermediate 3 in Example 2, in anhydrous DMF (15mL), was added Intermediate 13 followed by Et₃N (0.41 mL, 2.94 mmol) andCuI (56 mg, 0.294 mmol). The reaction mixture was bubbled with argon,followed by the addition of PdCl₂(PPh₃)₂ (104 mg, 0.147 mmol) underargon. The reaction solution was stirred at 80° C. for 16 h. Thereaction was cooled to room temperature and DMF was removed underreduced pressure. The residue was diluted with CH₂Cl₂ and the reactionmixture was quenched with water and extracted with CH₂Cl₂ (3×50 mL), thecombined organic layers were dried over MgSO₄, filtered andconcentrated. The crude product was purified on a column (MPLC) usinghexane:ethyl acetate and gave Compound 19 (145 mg).

¹H NMR (CD₃OD, 300 MHz) δ: 7.30-7.35 (m, 5H), 7.22-7.29 (m, 9H),6.97-7.07 (m, 7H), 6.93 (s, 1H), 6.83-6.88 (m, 1H), 3.92-4.13 (m, 5H),3.62-3.78 (m, 3H), 2.89-3.07 (m, 2H), 2.21 (d, J=2.9 Hz, 6H).

Compounds 20 and 21 were prepared in a similar manner to the methoddescribed in Example 15 for Compound 19. The starting materials and theresults are tabulated below in Table 6 for each case.

TABLE 6 Comp. ¹NMR (Solvent; δ number IUPAC name Starting material ppm)20

3,4-dimethyl benzaldehyde (CAS 68844-97-3) Benzeneacetonitrile,3-fluoro- (CAS 501-00-8) ¹H NMR (CDCl₃, 300 MHz) δ: 7.39 (d, J = 2.1 Hz,1H), 7.19-7.29 (m, 2H), 7.00-7.13 (m, 3H), 6.80- 6.99 (m, 4H), 4.07-4.17(m, 5H), 4.01 (t, J = 7.2 Hz, 1H), 3.79- 3.89 (br. s., 1H), 3.01 (d, J =7.3 Hz, 2H), 2.86 (br. s., 1H), 2.23 (s, 6H) 21

3,4-dimethyl benzaldehyde (CAS 68844-97-3) Benzene acetonitrile, 3-methyl- (CAS 2947-60-6) ¹H NMR (CD₃OD, 300 MHz) δ: 7.29 (d, J = 2.1 Hz,1H), 7.10-7.26 (m, 4H), 6.93- 7.08 (m, 4H), 6.82-6.91 (m, 1H), 3.92-4.18(m, 3H), 3.61-3.78 (m, 3H), 2.85- 3.05 (m, 2H), 2.32 (s, 3H), 2.20 (d,6H)

Example 16 Compound 22 for3-({4-[(1E)-4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-en-1-yl]benzyl}amino)propanoicacid

3-aminopropanoic acid (62 mg, 0.70 mmol) was added to a solution ofIntermediate 7 (167 mg, 0.466 mmol) in MeOH (10 mL) followed by AcOH (2drops) at room temperature. The reaction mixture was stirred at roomtemperature for 20 minutes then NaCNBH₃ (30 mg, 0.47 mmol) was added tothe reaction mixture in 2 mL MeOH. The reaction mixture was stirred atroom temperature for 2 h. The reaction mixture was then quenched withwater (1 mL) and celite was added concentrated to dryness, then purifiedby reverse phase MPLC using CH₃CN:H₂O and gave Compound 22 (84 mg).

¹H NMR (CD₃OD, 300 MHz) δ: 7.35 (s, 4H), 7.20-7.30 (m, 1H), 6.83-7.05(m, 5H), 6.74-6.83 (m, 1H), 6.39-6.53 (m, 1H), 6.24-6.32 (m, 1H), 4.11(s, 2H), 3.71 (q, J=7.6 Hz, 1H), 3.11 (t, J=6.3 Hz, 2H), 2.89-3.04 (m,2H), 2.48 (t, J=6.4 Hz, 2H), 2.13 (s, 6H).

Example 17 Compound 23[3-({4-[(1E)-4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-en-1yl]benzyl}amino)propyl]phosphonicacid

Intermediate 7 (195 mg, 0.55 mmol) was dissolved in Methanol (6 mL) at50° C. (3 aminopropyl)phosphonic acid (77 mg, 0.55 mmol) was addedfollowed by tert-butyl ammonium hydroxide (0.55 ml, 1.0 M in MeOH). Thereaction mixture was stirred for 30 minutes until it became a clearsolution. Sodium cyano borohydride (35 mgs, 0.55 mmol) was added and thereaction was stirred at 50° C. for 3 hours. Then the reaction mixturewas cooled to room temperature and silica gel was added concentrated todryness, and then purified on a column (MPLC) using CH₂Cl₂:MeOH and gaveCompound 23 (54 mg).

¹H NMR (CD₃OD, 300 MHz) δ: 7.31-7.44 (m, 4H), 7.25 (td, J=7.9, 6.2 Hz,1H), 6.81-7.06 (m, 5H), 6.75-6.81 (m, 1H), 6.40-6.53 (m, 1H), 6.19-6.34(m, 1H), 4.04 (s, 2H), 3.72 (d, J=7.9 Hz, 1H), 2.90-3.10 (m, 4H), 2.14(s, 6H), 1.95 (ddd, J=17.8, 6.9, 6.7 Hz, 2H), 1.56-1.76 (m, 3H).

Biological Data

Compounds were synthesized and tested for S1P1 activity using the GTPγ³⁵S binding assay. These compounds may be assessed for their ability toactivate or block activation of the human S1P1 receptor in cells stablyexpressing the S1P1 receptor.

GTP γ³⁵S binding was measured in the medium containing (mM) HEPES 25, pH7.4, MgCl₂ 10, NaCl 100, dithitothreitol 0.5, digitonin 0.003%, 0.2 nMGTP γ³⁵S, and 5 μg membrane protein in a volume of 150 μl. Testcompounds were included in the concentration range from 0.08 to 5,000 nMunless indicated otherwise. Membranes were incubated with 100 μM5′-adenylylimmidodiphosphate for 30 min, and subsequently with 10 μM GDPfor 10 min on ice. Drug solutions and membrane were mixed, and thenreactions were initiated by adding GTP γ³⁵S and continued for 30 min at25° C. Reaction mixtures were filtered over Whatman GF/B filters undervacuum, and washed three times with 3 mL of ice-cold buffer (HEPES 25,pH7.4, MgCl₂ 10 and NaCl 100). Filters were dried and mixed withscintillant, and counted for ³⁵S activity using a β-counter.Agonist-induced GTP γ³⁵S binding was obtained by subtracting that in theabsence of agonist. Binding data were analyzed using a non-linearregression method. In case of antagonist assay, the reaction mixturecontained 10 nM S1P in the presence of test antagonist at concentrationsranging from 0.08 to 5000 nM.

Table 7 shows activity potency: S1P1 receptor from GTP γ³⁵S: nM, (EC₅₀)Activity potency: S1P1 receptor from GTP γ³⁵S: nM, (EC₅₀).

TABLE 7 S1P1 IUPAC name EC₅₀ (nM)[3-({4-[(1E)-4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1- 172en-1-yl]benzyl}amino)propyl]phosphonic acid3-({4-[(1E)-4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1- 265en-1-yl]benzyl}amino)propanoic acid3-{2-chloro-4-[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)but- 2381-yn-1-yl]phenoxy}propane-1,2-diol3-{2-chloro-4-[4-(3,4-dimethylphenyl)-3-(3-methylphenyl)but- 4011-yn-1-yl]phenoxy}propane-1,2-diol3-{2-chloro-4-[4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but- 6001-yn-1-yl]phenoxy}propane-1,2-diol3-{4-[3-(3-Chloro-phenyl)-4-(3,4-dimethyl-phenyl)-but-1- 262ynyl]-3-methyl-benzylamino}-propionic acid(3-{4-[3-(3-Chloro-phenyl)-4-(3,4-dimethyl-phenyl)-but-1- 75.4ynyl]-benzylamino}-propyl)-phosphonic acid(3-{4-[4-(3,4-Dimethyl-phenyl)-3-(3-methoxy-phenyl)-but-1- 160ynyl]-benzylamino}-propyl)-phosphonic acid(3-{4-[4-(3,4-Dimethyl-phenyl)-3-m-tolyl-but-1-ynyl]- 117benzylamino}-propyl)-phosphonic acid(3-{4-[3-(3-Chloro-phenyl)-4-(3,4-dimethyl-phenyl)-but-1- 17.7ynyl]-3-methyl-benzylamino}-propyl)-phosphonic acid3-({4-[4-(3,4-dimethylphenyl)-3-(3-methoxyphenyl)but-1-yn- 2471-yl]benzyl}amino)propanoic acid3-({4-[4-(3,4-dimethylphenyl)-3-(3-methylphenyl)but-1-yn-1- 502yl]benzyl}amino)propanoic acid3-({4-[3-(4-chlorophenyl)-4-(3,4-dimethylphenyl)but-1-yn-1- 480yl]benzyl}amino)propanoic acid3-({4-[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)but-1-yn-1- 66yl]benzyl}amino)propanoic acid[3-({4-[4-(3,4-dimethylphenyl)-3-(3-methylphenyl)but-1-yn-1- 56 yl]-3methylbenzyl}amino) propyl]phosphonic acid[3-({4-[4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-yn-1- 1894yl]-3-methylbenzyl}amino) propyl]phosphonic acid[3-({3-bromo-4-[4-(3,4-dimethylphenyl)-3-(3- 6fluorophenyl)but-1-yn-1-yl]benzyl}amino) propyl]phosphonic acid[3-({4-[4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-yn-1- 239yl]-3-(2-furyl)benzyl}amino) propyl]phosphonic acid[3-({4-[4-(3,4-dimethylphenyl)-3-(3-methylphenyl)but-1-yn-1- 179yl]-3-(2-thienyl)benzyl}amino) propyl]phosphonic acid[3-({3-bromo-4-[3-(3,5-difluorophenyl)-4-(3,4- 31dimethylphenyl)but-1-yn-1-yl]benzyl}amino) propyl]phosphonic acid[3-({4-[4-(3,4-dimethylphenyl)-3-(3-methylphenyl)but-1-yn-1- 59yl]-3-(2-furyl)benzyl}amino) propyl]phosphonic acid

What is claimed is:
 1. A compound having Formula I, its enantiomers,diastereoisomers, or a pharmaceutically acceptable salt thereof,

wherein: “

” represents a double bond “—CR¹⁴═CR¹⁵—”; A is C₆₋₁₀ aryl, heterocycle,C₃₋₈ cycloakyl or C₃₋₈ cycloalkenyl; B is C₆₋₁₀ aryl, heterocycle, C₃₋₈cycloakyl or C₃₋₈ cycloalkenyl; R¹ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈alkyl, CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl; R² is H, halogen, —OC₁₋₈ alkyl,C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl; R³ is H, halogen, —OC₁₋₈alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl; R⁴ is H, halogen,—OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl; R⁵ is H,halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl; R⁶is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl; R⁷ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, C₆₋₁₀aryl, heterocycle, C₃₋₈ cycloakyl, C₃₋₈ cycloalkenyl, NR¹²R¹³ orhydroxyl; R⁸ is the same or independently halogen, —OC₁₋₈ alkyl, C₁₋₈alkyl, CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl; L¹ is O, S, NH or CH₂; R⁹ is Hor C₁₋₆ alkyl; L² is CHR¹⁴ or O; R¹⁰ is H, OPO₃H₂, carboxylic acid,hydroxyl, PO₃H₂, —S(O)₂H, —P(O)MeOH or —P(O)(H)OH; R¹¹ is H or C₁₋₈alkyl; a is 0, 1, 2 or 3; b is 0 or 1; R¹² is H or C₁₋₈ alkyl; R¹³ is Hor C₁₋₈ alkyl; R¹⁴ is H, hydroxyl or C₁₋₈ alkyl; R¹⁵ is H or C₁₋₈ alkyl;R¹⁶ is O, S, C(O) or CH₂; and c is 0 or 1; with the proviso that thecompound of Formula I is not of structure


2. A compound according to claim 1, wherein: “

” represents a double bond “—CR¹⁴═CR¹⁵—”.
 3. A compound according toclaim 1, wherein: L¹ is CH₂.
 4. A compound according to claim 1,wherein: L¹ is O, S or NH.
 5. A compound according to claim 1, wherein:


6. A compound according to claim 1, wherein: “

” represents a double bond “—CR¹⁴═CR¹⁵—”;

R¹ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl; R² is H, halogen, —OC₁₋₆alkyl or C₁₋₆ alkyl; R³ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl; R⁴ isH, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl; R⁵ is H, halogen, —OC₁₋₆ alkylor C₁₋₆ alkyl; R⁶ is H, halogen, —OC₁₋₆ alkyl or C₁₋₆ alkyl; R⁷ is H,halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, C₆ aryl, heterocycle, C₃₋₈ cycloakylor C₃₋₈ cycloalkenyl; R⁸ is halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN,C(O)R¹¹, NR¹²R¹³ or hydroxyl; L¹ is CH₂; R⁹ is H or C₁₋₆ alkyl; L² isCHR¹⁴; R¹⁰ is carboxylic acid or PO₃H₂; R¹¹ is H or C₁₋₆ alkyl; a is 0or 1; b is 1; R¹² is H or C₁₋₆ alkyl; R¹³ is H or C₁₋₆ alkyl; R¹⁴ is Hor C₁₋₆ alkyl; R¹⁵ is H or C₁₋₆ alkyl; R¹⁶ is CH₂; and c is 0 or
 1. 7. Acompound according to claim 1, selected from:[3-({4-[(1E)-4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-en-1-yl]benzyl}amino)propyl]phosphonicacid; and3-({4-[(1E)-4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-en-1-yl]benzyl}amino)propanoicacid.
 8. A pharmaceutical composition comprising as active ingredient atherapeutically effective amount of a compound according to claim 1, anda pharmaceutically acceptable adjuvant, diluents or carrier.
 9. Apharmaceutical composition according to claim 8, wherein the compound isselected from:[3-({4-[(1E)-4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-en-1-yl]benzyl}amino)propyl]phosphonicacid; and3-({4-[(1E)-4-(3,4-dimethylphenyl)-3-(3-fluorophenyl)but-1-en-1-yl]benzyl}amino)propanoicacid.